The preservatives in eye drops, especially benzalkonium chloride (BAK), have been shown to be damaging to ocular surface tissues especially meibomian glands, goblet cells, and lacrimal glands. BAK was first FDA approved in the 1950’s. Those patients who have used BAK extensively may be the same patients we are seeing now with significant Meibomian gland atrophy.
The following are the most commonly used preservatives and eyedrop‘s. Since the eye tissues are so delicate, all of these are likely causing damage if such preservative drops are used chronically. How quickly preserved drops will cause damage and eye symptoms depends on many factors such as the age of the patient, what other eye drops & medications (ie like isotretinoin) being used, general heath, genetics, total electronic screen time, other risk factors like the presence of rosacea, contact lens use, diabetes, auto immune disease (ie thyroid disease, rheumatoid arthritis, Lupus, Sjögren’s syndrome), history of eye surgery, presence of pterygia or pinguecula, other heath issues (ie, anemia, GERD, h/o gallbladder removal).
We generally recommend Non preserved artificial tears like Refresh Plus, Refesh MGD, Systane, Optase, Theratears for this reason but often these do not help enough as they are not anti-inflammatory nor healing like one’s own autologous serum or platelet rich plasma. Prescription anti-inflammatory drops like Lifitegrast and cyclosporine can help many patients though about 30% find them irritating and cannot tolerate them which can happen even with AS or PRP though less than 1% risk in our sample.
Here is a list of most commonly used preservatives in eye drops:
1. Benzalkonium Chloride (BAK): The most commonly used preservative, effective but known to cause irritation and damage to the ocular surface with long-term use.
2. Polyquaternium-1 (Polyquad): A less irritating preservative compared to BAK, often used in newer formulations.
3. Sodium Perborate: Converts to hydrogen peroxide in the eye, providing antimicrobial action. Generally considered less irritating.
4. Purite (Stabilized Oxychloro Complex): Breaks down into natural tear components (water and salt) on the ocular surface, making it less irritating.
5. Sorbic Acid: Another preservative that is used in some eye drop formulations.
6. Thimerosal: Contains mercury and is less commonly used due to potential for irritation and allergic reactions.
7. Chlorobutanol: Used less frequently, it has both antimicrobial and anesthetic properties.
8. Ethylenediaminetetraacetic Acid (EDTA): Often used in combination with other preservatives to enhance their efficacy.
9. Methylparaben and Propylparaben: Used in combination in some formulations, though less common due to potential allergenic properties.
10. Chlorhexidine: Sometimes used in eye drop formulations, but can also cause irritation with prolonged use.
11. Phenoxyethanol: Occasionally used, less common than BAK or Polyquad.
12. Benzododecinium Bromide: Similar to BAK, used in some formulations.
Each of these preservatives has its own profile in terms of efficacy and potential for causing ocular irritation or damage, especially with long-term use. Preservative-free or single-use vials are often recommended for those with sensitive eyes or who require frequent use of eye drops.
Here are a few of the published reports:
Preservatives Damage Meibomian Gland Cells:
1. Chonnam Med J. 2019 Sep; 55(3): 156–162.
Effects of Preservative on the Meibomian Gland in Glaucoma Patients Treated with Prostaglandin Analogues
Key points from paper:
A. 0.001% BAK was enough to induce MG damage
B. The most frequently used preservative, BAK, has been demonstrated to have toxic effects on many ocular structures in laboratory, experimental, and clinical studies.19,20,21 It has been shown to cause:
- tear film instability,
-loss of goblet cells,
-conjunctival squamous metaplasia
-cell death aka: apoptosis,
-disruption of the corneal epithelium barrier,
- damage to deeper ocular tissues.19
C. In vitro studies note the cytotoxic effects of BAK on the human MG epithelial cells occur at very low concentrations (0.00001%)
D. In vivo confocal microscopy studies show meibomian gland acinar (the structure of the gland) dropout and inflammation were much less evident in patients with low cumulative doses of preservatives.22 The potential mechanisms are direct toxicity and a secondary inflammatory or immune-mediated response, with inflammation probably being the first step in the cascade of glandular modifications leading to acinar dropout.
E. If you combine a medication with the preservative such as in glaucoma medications, they can have an additive effect.23.5,13,22\
F. The preservative BAK may enhance these effects of the PGA active component by promoting the drug's penetration into the glands.24 Since MGs are located in the tarsal plate of the eyelid, which is at a relatively deeper position than that of the superficial ocular surface, theoretically, resistance is higher in MGs than in superficial ocular structures. However, owing to BAK, toxicity and inflammation of the conjunctiva can easily diffuse into the MGs.
G. “….Studies have found that long-term use of glaucoma eye drops affected morphology and function of the meibomian gland, irrespective of the number or type of medication. Arita et al. (Arita R, Itoh K, Maeda S, Maeda K, Furuta A, Tomidokoro A, et al. Effects of long-term topical anti-glaucoma medications on meibomian glands. Graefes Arch Clin Exp Ophthalmol. 2012;250:1181–1185. [PubMed] ) reported similar meibomian gland dropout in PGA and beta-blocker treated eyes. It is speculated that rather than active components, preservative such as benzalkonium chloride (BAK) may exert a primary and dose-dependent toxic effect on MG. These findings are supported by multiple experimental and clinical studies that demonstrate that preservative free PGAs (PF-PGAs) induce lower MG damage than preservativecontaining PGAs (PC-PGAs). Rath A, Eichhorn M, Träger K, Paulsen F, Hampel U. In vitro effects of benzalkonium chloride and prostaglandins on human meibomian gland epithelial cells. Ann Anat. 2019;222:129–138. [PubMed] [Google Scholar]
2. Noecker R. Effects of common ophthalmic preservatives on ocular health. Adv. Ther. 2001;18:205–215. doi: 10.1007/BF02853166.
3. Preservatives in Topical Ophthalmic Medications: Historical and Clinical Perspectives, by Paul T. Finger et al. This review provides an overview of the historical use of preservatives in eye drops and their clinical implications. Ocular Surface* (2007), Vol. 5, No. 3.
4. The effects of preservatives in eye drops on the ocular surface by Christophe Baudouin.The study examines how preservatives, particularly BAK, can cause toxicity and inflammation in ocular surface tissues. Current Opinion in Ophthalmology (2005), Vol. 16, No. 4.
5. The impact of preservatives and preservatives-free artificial tears in patients with dry eye disease"** by Gregory L. Skorin Jr. This article discusses how preservatives in artificial tears can exacerbate dry eye disease by damaging ocular surface cells and glands. Clinical Ophthalmology (2014), Vol. 8.
6. Toxicity of preservatives in eye drops to human ocular surface cells: Evaluation of apoptosis using annexin V stainingby Denis De Saint Jean et al. This research evaluates the apoptotic effects of preservatives like BAK on human ocular surface cells. Investigative Ophthalmology & Visual Science* (1999), Vol. 40, No. 3.
7. Ocular toxicity of topical preservatives by Christophe Baudouin et al. This comprehensive review highlights the toxic effects of various preservatives on the ocular surface, emphasizing the impact on meibomian glands and tear film stability. Survey of Ophthalmology (1994), Vol. 38, Suppl. 1.
8. Preservative-induced ocular surface changes: Implications for allergy diagnosis and treatment"** by Josep M. Benítez-Del-Castillo et al. The study explores how preservatives in allergy eye drops can lead to ocular surface changes and impact treatment outcomes. Current Opinion in Allergy and Clinical Immunology* (2019), Vol. 19, No. 5.
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